Hydralazine (e.g., Apresoline brand) is used to treat arterial hypertension (primary; malignant; pulmonary; pre-eclampsia and eclampsia), congestive heart failure, pulmonary hypertension in chronic obstructive pulmonary disease, and aortic regurgitation (McFadden, E R Jr & Braunwald, E., “Cor pulmonale,” p. 1581-1601, Heart Diseases. A Textbook of Cardiovascular-Medicine (4th ed.) (Philadelphia: W B Saunders, 1992); Gallagher, M W; Repke, J T & Goldstein, P J (1994), “Pharmacologic Approach to the Critically Ill Obstetric Patient,” p: 847-862, The Pharmacologic Approach to the Critically Ill Patient (3rd ed.), Chernow, B (ed.) (Oates, I A: Williams & Wilkins, 1995); Antihypertensive Agents and Drug Therapy of Hypertension, Goodman & Gilman's The Pharmacological Basis of Therapeutics (9th ed.), p. 809-838, Hardman, Limbird; Molinoff, Ruddon, and Gilman (eds.), (New York: McGraw/Hill); Chatterjee et al., Ann. Intern. Merl, Vol. 92, pp. 600-604 (1980); and Franciosa et al, Am. Heart .1, Vol. 104, pp. 587594 (1982). Some benefit may be seen if used in primary esophageal motility disorders (Mellow, M H, “Effect of isosorbide and hydralazine in painful primary esophageal motility disorders”, Gastroenterology, 83:364-370 (1982)) and psoriasis (Isaac, P., “Hydralazine and psoriasis,” Br. Med. J., 285:744 (1982)). Recent observations indicate hydralazine can be used to withdraw patients from dobutamine in severe congestive heart failure (Binkley P F., et al., “Usefulness of hydralazine to withdraw from dobutamine in severe congestive heart failure,” Am. Cardia, 68:1103-1106 (1991)). Infants with chronic heart failure and left-to-right shunts may experience some benefit with hydralazine use (Artman, M, et al., “Short-term hemodynamic effects of hydralazine in infants with complete arterioventricular canal defects,” Circulation, 69:949-954 (1984)).
Uses of hydralazine along with other drugs have been reported by Jay Cohn et al. (U.S. Pat. Nos. 4,868,179, 6,784,177, and 6,465,463) for treating and preventing mortality associated with heart failure, improving oxygen consumption, quality of life and/or exercise tolerance in a black patient with hypertension.
Hydralazine hydrochloride is an artery specific direct peripheral vasodilator drug used to treat essential hypertension and it is commercially available in both oral and injectable dosage forms in the U.S. and other countries. Hydralazine hydrochloride is a drug having an onset of action with oral administration between 10-30 minutes (10-20 minutes given intravenously), a maximum hypotensive effect in 10-80 minutes, and duration of action between 3-4 hours.
Despite approval by the U.S. Food and Drug Administration (FDA) for administration of 20 mg hydralazine hydrochloride injectable doses, several clinical hazards are reported with the currently available hydralazine injectable formulations. Stability of the sterile injection solution is a serious problem due to the formation of particles in the hydralazine sterile injection solutions during storage for more than six months. These stability issues with hydralazine hydrochloride injectable solutions are likely due to the minor impurities present in the drug.
Donald has described in U.S. Patent Pub. 2003/0212272 that an injectable formulation of hydralazine forms small yellow-green particles following storage for one to two months at 40° C., and similarly after storage for six to nine months at 25° C. Although the identification of the yellow-green particles has yet to be confirmed, it is believed that the particles are insoluble polymeric products formed during storage of hydralazine—that the compound undergoes degradation in stored sterile injectable solutions, forming insoluble polymeric products because of the highly reactive hydrazino group. Hydralazine hydrochloride also undergoes several pharmaceutically undesirable reactions such as chelation with metal ions, oxidation, and pH-dependent decomposition. It is believed that these reactions, which often cause discoloration of hydralazine compositions, are also due to the highly reactive hydrazino group. Lessen et al., J. Pharmaceutical Sci., 85(3): 326-329(1996), report that, in addition to the usual hydralazine degradants such as phthalazone and phthalazine, tablet compositions produced triazolophthalazine derivatives. Sinha and Motten, in Biochemical and Biophysical Research Communications 105(3). 1044-1051 (1982), report that hydralazine oxidizes rapidly in the presence of oxygen and metal compounds such as Cu+2, Fe+2, and Fe+3 through free radical intermediates, much like other hydrazine derivatives.
As described in the art, the hydralazine drug molecule is sensitive to excipients reactive with its hydrazine moiety. In addition to excipients, impurities present in the drug substance play a key role in causing instability of sensitive molecules such as hydralazine. Thermal degradation and hydrolysis of hydralazine gives phthalazinone, phthalazine, and triazolophthalazine. Producing hydralazine hydrochloride in significantly purer form would significantly improve the stability of the product and thus maintain its safety and efficacy.
The first process of preparing hydralazine (1-hydrazinophthalazine) and its salts was reported in U.S. Pat. No. 2,484,029 and British Pat. No. 629,177. This process involved the preparation of 1-chlorophthalazine (from phthalazinone by the process reported in Ber. D. deutsch. chem. Ges., Vol., 26, page 521 (1893)), and the freshly obtained yet moist chloro compound was further reacted with a mixture of 100 parts by volume of ethyl alcohol and 90 parts by volume of hydrazine hydrate. The hydralazine thus obtained was recrystallized from methanol and converted to the hydrochloride salt on warming in alcoholic or aqueous hydrochloric acid. Hydralazine hydrochloride obtained by this process is found to contain several impurities at about 0.5%, has a greater than 0.01% level of hydrazine content, and does not comply with the present pharmacopoeial requirements for the drug. The U.S. Pharmacopoeia requires the hydralazine drug substance to be free of hydrazine at a level less than 0.001%, and the European Pharmacopoeia requires any individual impurities to be present at levels not more than 0.2%.
More recently, U.S. Patent Pub. 2005/0137397 (the '397 application) discloses the process of preparing hydralazine hydrochloride involving the preparation of chlorophthalazine from phthalazinone and phosphorous oxychloride, separating using a first solvent such as an alkane having 5 to 7 carbons and a second solvent (such as tetrahydrofuran), reacting the isolated chlorophthalazine with hydrazine in presence of alcohol to produce hydralazine, and treating the hydralazine with hydrochloric acid to yield hydralazine hydrochloride. It is disclosed that the product hydralazine hydrochloride obtained by this process contains phthalazine impurities less than 0.5% and hydrazine content less than 0.0005%.
The process of the '397 application has a number of drawbacks. The chlorophthalazine prepared as disclosed in this publication was found to contain more insoluble matter. In addition, the process of isolating chlorophthalazine, as disclosed in this publication, involves decanting a supernatant liquid mixture containing several volumes of hexane and phosphorous oxychloride, a cumbersome operation and that is a serious limitation towards scaling-up the disclosed process. The description in the '397 application of the hydralazine hydrochloride produced is pale yellow in color, and off-white after recrystallization from ethanol.
There is no reported procedure in the art for the purification of hydralazine to remove the yellow color and for the reduction of hydrazine content to a level of below 0.001%.
Hydralazine hydrochloride is one of the drugs known for its instability in injectable solution during storage. This problem calls for the need of a process to produce hydralazine hydrochloride free of significant level of impurities and for the need of a process of purification of impure hydralazine hydrochloride